Axl (also known as: UFO, ARK, Tyro7) is a receptor tyrosine kinase belonging to a TAM family (Axl, Mer and Tyro3) cloned from tumor cells. Gas6 (growth-arrest-specific protein 6) cloned as a gene specifically expressed at the time of cell proliferation arrest is known as a ligand for Axl. Axl activated by binding of Gas6 transfers a signal via phosphorylation. Since the signal activates an Erk1/2 pathway or a PI3K/Akt pathway, the activation of Axl is known to be involved in pathologic conditions of cancers, immune system diseases, circulatory system diseases, and the like (see, Non-Patent Literature 1).
In particular, the relation between Axl and various types of cancers is well known. For example, it is known that the expression of Axl is involved in metastasis and prognosis of breast cancer (see, Non-Patent Literature 2), and that Axl is involved in the pathologic conditions of acute myeloid leukemia (AML) (see Non-Patent Literature 3). Therefore, it is considered that compounds which inhibit the activation of Axl are useful for treatment of various type of cancers, immune system diseases, and circulatory system diseases.
By the way, as prior art of the compound of the present invention, a compound represented by general formula (A):
(wherein AA represents C—R10A and N; BA represents C—R11A and N; DA represents heterocycles of the following general formulae, and the like.
(wherein R1A, R4A and R88A are independently —H, —F, —Cl, —Br, —I, —OH, —NH2, —OCH3, —OC2H5, or the like; R2A and R3A are independently —R88A or the like; R5A and R6A may be the same as each other or different from each other, and represent —H, —F, —Cl, —Br, —I, —CN, —NO2, —CH3, or the like; R7A, R8A, R10A, and R11A may be the same as each other or different from each other, and represent —H, —F, —Cl, —Br, —I, —CN, —NO2, —CH3, or the like; R9A represents —H or the like; R12A represents —CN, phenyl, or the like; R13A represents —H, —F, —Cl, —Br, —I, —CN, —NO2, —CH3, or the like; R14A represents —H, —F, —Cl, —Br, —I, —NO2, —CN, or the like (where the definitions of the groups are excerpted)) is known to be an Axl inhibitor (see, Non-Patent Literature 1).
Furthermore, a compound represented by general formula (B):
(wherein EB and GB are independently a hydrogen atom, a C1-6 alkyl group optionally substituted with one to six R19B, a C6-11 aryl group optionally substituted with one to six R19B or the like; XB represents N or C—R4B; YB represents N or C—R1dB; DB represents —O—, —S—, —NH— or the like; WB represents CH or N; RaB, RbB, RcB, RdB, R1aB, R1cB, R1dB and R4B independently represent a hydrogen atom, —OR110B, or the like; R19B represents a halogen atom, —CN, or the like; and R110B represents a hydrogen atom, a C1-6 alkyl group optionally substituted with one to six R129B (where the definitions of the groups are excerpted)) is known to be an Axl inhibitor (see Patent Literature 2).
On the other hand, a compound having a quinoline skeleton and represented by the following general formula (C):
is known to have an ASK1 inhibitory activity, and be an agent for preventing and/or treating amyotrophic lateral sclerosis (ALS) (see Patent Literature 3).
Furthermore, a compound represented by general formula (D):RD—XD—WD—YD—R1D  (D)(wherein RD represents
or the like; TD represents phenyl or the like; ZD represents N or CR7D; WD represents a substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered nitrogen-containing heteroaryl or the like; XD represents O, S, S(═O), or the like; YD represents —NRaDC(═O)—(CR3DR4D)p— or the like; RaD represents, a hydrogen atom, an alkyl group, or the like; and R1D represents
or the like; J2D represents O or CR4aDR4aD; QD represents 1- to 5-membered saturated or partially unsaturated alkyl chain or the like; R1D represents optionally substituted phenyl or may be fused to optionally substituted 5- to 6-membered heterocycle; R3D and R4D each independently represents a hydrogen atom, an alkyl group, an aryl group, or the like; R4aD is absent or represents a hydrogen atom, a halogen atom, or the like (where the definitions of the groups are excerpted)) is known to be a c-Met inhibitor (see Patent Literature 4).
Furthermore, a compound represented by general formula (E):
(wherein R1E, R2E and R4E independently represent H, F, Cl, Br, I, CN, OR10E, C1-C12 alkyl, or the like; LE represents a C3-C12 carbon ring, C6-C20 aryl, or the like; R5E represents —C(═YE)R13E, —C(═YE)R10ER13E, —NR10EC(═YE)R13E, or the like; R10E represents H, C1-C12 alkyl, a C3-C12 carbon ring, a C2-C20 heterocycle, or the like; R13E represents H, C1-C6 alkyl, or the like; and YE represents O or S (where the definitions of the groups are excerpted)) is known to be a c-Met inhibitor (see Patent Literature 5).
However, any of the prior art literatures neither mention nor suggest that a quinoline derivative as a compound of the present invention, having a bicyclic structure in which a saturated carbon ring is fused to a pyridone ring, represented by the following structural formula.
has a significant Axl inhibitory activity.